Inhibiting a protein that regulates many signalling pathways in cancer cells is an attractive approach for cancer therapy. HSP90 is a molecular chaperone that regulates the function and stability of many important signalling proteins and has been implicated in the survival of tumour cells. The problem is that HSP90 is also present in normal cells, and there was concern that when the HSP90 inhibitor 17-AAG entered Phase I clinical trials, unacceptably toxic effects would be seen. However, 17-AAG seems to be well tolerated, and now Adeela Kamal et al. provide some explanations as to why — the drug only binds to HSP90 when in an activated state as part of a multichaperone complex.

Kamal and colleagues first showed that 17-AAG does have a higher affinity for HSP90 in tumour cells — in this case, BT474 breast carcinoma cells (IC50 6 nM) — than in normal cells (IC50 600 nM). 17-AAG specifically inhibits the ATP-binding site of HSP90, and the binding affinity of ATP was tenfold higher in the tumour cell lines. 17-AAG also had higher affinity for HSP90 in ERBB2-overexpressing cancer cell lines.

To understand how HSP90 differs between normal and tumour cells, the authors looked at the levels of two essential components of multichaperone HSP90 complexes — P23 and HOP — in the cell lines. They used immunoprecipitation assays to show that more HSP90 was present in complexes with P23 and HOP in tumour cells compared with normal cells. Tumour HSP90 also had markedly higher ATPase activity than HSP90 from normal cells.

So, why is it that 17-AAG has a higher affinity for HSP90 in tumour cells — is it because of the co-chaperones? In vitro reconstitution of purified HSP90 with HSP70, HSP40, P23 and HOP increased the affinity of 17-AAG from 600 nM for HSP90 alone to 12 nM for the complex. The in vitro observations were also borne out in vivo — in breast cancer and colon cancer human clinical materials.

The authors suggest that dependence of cancer cells on activated HSP90 could make the multichaperone complex a unique cancer target with great potential for exploitation in cancer therapy.